Iodinated organic compounds, in particular triiodophenyl monomer and dimer compounds, have long established and widespread commercial use as X-ray contrast agents. Initially, the commercially available compounds were ionic compounds (eg. metrizoate, iodipamide, iodamide, iobenzamate, iocarmate, iocetamate, iodoxamate, ioglicate, ioglycamate, iopanoate, iophendylate, iopronate, ioserate, iothalamate, iotroxate, ioxaglate and ioxitalamate) but more recently the dominant commercial iodinated X-ray contrast agents have been the non-ionic compounds (such as iohexol, iopamidol, iomeprol, iopentol, iopromide, iosimide, iotasul, iotrolan, ioversol, metrizamide and iodixanol) which may be administered parenterally at higher concentrations and with reduced adverse effects.
The non-ionic compounds derive their necessary water-solubility from the presence in their molecular structures of non-ionic solubilizing groups such as hydroxyalkyl groups. Thus by way of example, iohexol, iopentol and iodixanol have the monomeric and dimeric triiodophenyl structures incorporating solubilizing hydroxyalkyl groups that are shown below: ##STR1##
The preparation of such compounds involves the introduction of a 2,3-dihydroxypropylamino group at ring attached carbonyls. As described by Haavaldsen et al. in Acta Pharm Suec 20: 219-232 (1983), this is achieved by reacting 3-amino-1,2-propanediol (APD) with a ring attached carboxyl group. A similar reaction is discussed in US-A-4250113 (Nyegaard & Co.).
APD has thus been a critical reagent in the synthesis of the commercial 2,3-dihydroxypropylaminocarbonyl-triiodophenyl X-ray contrast agents.
There has however been a major problem in producing APD with sufficiently high purity (eg. .gtoreq.99.9%). One synthetic approach to APD production involves the reaction of glycidol (1-hydroxy-2,3-epoxypropane) with ammonia. Not only is this reaction potentially explosive but the reaction product is a mixture of APD and 2-amino-1,3-propanediol. Purification of the reaction product requires a very difficult distillation since the boiling point difference between the two aminodiols is very small.
An alternative approach has been to epoxidate allyl chloride, hydrolyse to produce 1-chloro-2,3-propanediol, and displace the chlorines with ammonia to yield APD. However, the basic conditions used can lead to reformation of the epoxide with the reaction with ammonia then yielding some of the undesired 2-amino product. Again therefore the difficult distillation is required to yield high purity APD.
A further approach has been to avoid the use of epoxides altogether and generate the diol group directly from an allyl group by oxidation with osmium tetroxide (see U.S. Pat. No. 5,191,119 (Cook Imaging)). This approach however involves use not only of osmium tetroxide but, as an intermediate, of isophthaloyl chloride. Synthesis of isophthaloyl chloride is an environmentally unfriendly reaction and the use of the highly poisonous osmium tetroxide in one of the final preparative steps for a product which is to be injected into patients is unacceptable.